Neuropathic pain (NP) is a chronic pain condition caused by somatosensory nervous system damage or disease, often imposing a significant economic burden. Current treatments are often ineffective and may cause side effects or dependency, highlighting the need for an improved understanding of NP pathology. We constructed a comprehensive NP single‐cell atlas categorizing 35,624 cells into nine types. Combined with multiomics analysis, it was found that the proportion of microglia increased in the NP group, while the proportion of oligodendrocytes (oligos) decreased. The Srp14 + Flt1 + microglial subpopulation in the NP group showed increased abundance and exacerbated inflammation via the PI3K‐Akt pathway. The Gstp1 + oligo subpopulation in NP was associated with transcriptional features indicative of cell cycle inhibition. Further through artificial intelligence virtual screening, we found that lumacaftor, dihydroergotamine, and the newly designed small molecule 1866 can stably bind to the Flt1 protein, supporting their potential as candidate compounds targeting Flt1 for further evaluation in NP models. This study not only reveals the key roles of microglia and oligos in NP neuropathy, but also, based on these findings, identifies experimentally verifiable candidate biomarkers and computationally derived drug leads with translational potential, offering new strategies for the precise treatment of NP.
Lu et al. (Thu,) studied this question.